1,6 naphthyridines useful as inhibitors of SYK kinase

Abstract

Disclosed are compounds of formula (I): wherein R 3 , R 5 , R 7 and R 8 are defined herein, which are useful as inhibitors SYK kinase and are thus useful for treating diseases resulting from inappropriate mast cell activation, which include allergic and inflammatory diseases. Also disclosed are pharmaceutical compositions comprising these compounds and processes for preparing these compounds.

What is claimed is:  
     
         1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 3  is H, C 1-3 alkyl, halogen or phenyl;  
 R 5  is N(R 9  )(R 10 ) or OR 11  , wherein 
 R 9  is H or C 1-3 alkyl,  
 R 10  is aminoC 2-6  alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 10  is C 3-7 cycloalkyl, heterocycloalkyl, heteroaryl, C 3-7 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl, arylC 1-4 alkyl or heteroarylC 1-4 alkyl each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, or R 9  and R 10  together with the nitrogen they are bonded to may form a heterocycloalkyl group containing one or more heteroatoms which is optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diCi 1-4 alkylamino, aminoCl 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, and  
 R 11  is aminoC 2-6 alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 11  is C 3-7 cycloalkyl, heterocycloalkyl, heteroaryl, C 3-7 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl, arylC 1-4 alkyl or heteroarylC 1-4 alkyl each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;  
 
 R 7  is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, (C 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, (diC 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido or heterocycloalkyl groups, or with a phenyl group which is optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diCi 1-3 alkylaminoC 1-3 alkyl, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups; and  
 R 8  is H, halogen or cyano.  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein: 
 R 3  is H or methyl;  
 R 5  is N(R 9 )(R 10  ) or OR 11  wherein 
 R 9  is H or methyl,  
 R 10  is aminoC 2-6 alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 10  is C 4-7 cycloalkyl, heterocycloalkyl selected from pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl, pyridyl and pyrimidinyl, C 3-6 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl wherein said heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, tetrahydrofuranyl and piperazinyl, phenylC 1-4 alkyl or heteroarylC 1-4 alkyl wherein said heteroaryl is selected from pyridyl, furyl, and imidazolyl, each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, or R 9  and R 10  together with the nitrogen they are bonded to may form a heterocycloalkyl group selected from piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl which is optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, and  
 R 11 , is is aminoC 2-6 alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 11  is C 5-7 cyclohexyl, heterocycloalkyl selected from pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl, pyridyl and pyrimidinyl, C 3-6 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl wherein said heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, tetrahydrofuranyl and piperazinyl, phenylC 1-4 alkyl or heteroarylC 1-4 alkyl wherein said heteroaryl is selected from pyridyl, furyl, and imidazolyl, each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;  
 
 R 7  is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, (C 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, (diC 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, C 1-3 alkylthio, aminocarboxy, ureido optionally substituted with C 1-3 alkyl, acetamido or heterocycloalkyl groups, or with a phenyl group which is optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups; and  
 R 8  is H;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . The compound according to  claim 1  wherein: 
 R 3  is H or methyl;  
 R 5  is N(R 9 )(R 10  ) or OR 11  wherein 
 R 9  is H or methyl,  
 R 10  is aminoC 2-6 alkyl, methylaminoC 2-6 alkyl, dimethylaminoC 2-6 alkyl, methoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen or sulfur, and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a hydroxy group, or R 10  is C 4-7 cycloalkyl, heterocycloalkyl selected from pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl, pyridyl and pyrimidinyl, C 3-6 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl wherein said heterocycloalkyl is selected from, pyrrolidin-2-onyl and piperidinyl, benzyl or heteroarylC 1-4 alkyl wherein said heteroaryl is selected from pyridyl and imidazolyl, each optionally substituted with one or more amino, aminomethyl, methylaminomethyl, dimethylaminomethyl, hydroxy, aminocarboxy or benzyl groups, or R 9  and R 10  together with the nitrogen they are bonded to may form a heterocycloalkyl group selected from piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl which is optionally substituted with one or more amino, hydroxy or aminocarboxy groups, and  
 R 11  is aminoC 2-6 alkyl, methylaminoC 2-6 alkyl, dimethylaminoC 2-6 alkyl, methoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen or sulfur, and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a hydroxy group, or R 11  is C 5-7 cycloalkyl, heterocycloalkyl selected from pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl, pyridyl and pyrimidinyl, C 3-6 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl wherein said heterocycloalkyl is selected from, pyrrolidin-2-onyl and piperidinyl, benzyl or heteroarylC 1-4 alkyl wherein said heteroaryl is selected from pyridyl and imidazolyl, each optionally substituted with one or more amino, aminomethyl, hydroxy, aminocarboxy, benzyl, methylaminomethyl, or dimethylaminomethyl groups;  
 
 R 7  is phenyl, optionally substituted in the 3-, 4-or 5-positions with one or more methoxy, fluorine, chlorine, bromine, CF 3 , CF 3 O, C 1-3 alkyl, diC 1-3 alkylamino, diC 1-3 alkylaminoC 1-3 alkyl, (C 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, (diC 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, thiomethoxy, acetamido, 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl groups, or substituted in the 4-position with a phenyl group optionally substituted in the 4-position with a methyl, methoxy, 2-thienyl or 3-pyridyl group, or R 7  is a 2-naphthyl or 2-thienyl group or a 5-indoyl group optionally substituted in the 1-position with a CF 3 , C 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, or C 1-3 alkylaminoC 1-3 alkyl group;  
 R 8  is H;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . The compound according to  claim 1  wherein: 
 R 3  is H;  
 R 5  is N(R 9 )(R 10 ) or OR 11  wherein 
 R 9  is H or methyl,  
 R 10  is aminoC 3-4 alkyl or hydroxyC 3-4 alkyl wherein each methylene group in said C 3-4 alkyl is optionally substituted with a hydroxy group, or R 10  is C 5-7 cycloalkyl substituted with an amino or hydroxy group, and  
 R 11  is aminoC 3-4 alkyl or hydroxyC 3-4 alkyl wherein each methylene group in said C 3-4 alkyl is optionally substituted with a hydroxy group, or R 11  is C 5-7 cycloalkyl substituted with an amino or hydroxy group;  
 
 R 7  is phenyl, substituted in the 4-position with a diC 1-2 alkylamino, (dimethylaminoC 2-3 alkyl)(Co 3 alkyl)amino, isopropyl, 4-morpholinyl, 4-piperidinyl or 4-pyrrolidinyl group and optionally substituted in the 3-position with a chlorine, bromine or methoxy group; and  
 R 8  is H;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . A compound selected from the group  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         6 . A compound selected from the group  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         7 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 5 .  
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 6 .  
     
     
         10 . A method for modulating the effects of a disease mediated by SYK kinase in a warm-blooded animal comprising administering to the animal a therapeutically effective amount of a compound as recited in  claim 1 .  
     
     
         11 . A method for modulating the effects of allergic or inflammatory disease in a warm-blooded animal comprising administering to the animal a therapeutically effective amount of a compound as recited in  claim 1 .  
     
     
         12 . The method according to  claim 11  wherein the allergic or inflammatory disease is selected from asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease bronchitis, conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis, allergic rhinitis, lupus and rheumatoid arthritis.  
     
     
         13 . A method of making a compound of formula (I) below:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  is H, C 1-3 alkyl, halogen or phenyl;  
 R 5  is N(R 9 )(R 10 ) wherein 
 R 9  is H or C 1-3 alkyl;  
 R 10  is aminoC 2-6 alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 10  is C 3-7 cycloalkyl, heterocycloalkyl, heteroaryl, C 3-7 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl, arylC 1-4 alkyl or heteroarylC 1-4 alkyl each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, or R 9  and R 10  together with the nitrogen they are bonded to may form a heterocycloalkyl group containing one or more heteroatoms which is optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;  
 
 R 7  is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, (C 1-   3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, (diC 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido or heterocycloalkyl groups, or with a phenyl group which is optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups; and  
 R 8 is H;  
 said method comprising: 
 (a) reacting the compound of formula (II) with a nitrile of the formula R 7 CN in the presence of a strong base in a suitable solvent to form a compound of formula (III):  
                     
 (b) reacting the compound of formula (III) with a suitable chlorinating agent to form the compound of formula (IV):  
                     
 (c) reacting the compound of formula (IV) with an amine of the formula HN(R 8 )(R 9 ) to provide the desired compound of formula (I) wherein R 5  is N(R 8 )(R 9 ) and R 8  is H:  
                     
 
 
     
     
         14 . A method of making a compound of formula (I) below:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  is H, C 1-3 alkyl, halogen or phenyl;  
 R 5  is OR 11  wherein 
 R 11  is aminoC 2-6 alkyl, C 1-4 alkylaminoC 2-6 alkyl, diC 1-4 alkylaminoC 2-6 alkyl, C 1-4 alkoxyC 2-6 alkyl or hydroxyC 2-6 alkyl, wherein one methylene group in said C 2-6 alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH 3 , and wherein each methylene group in said C 2-6 alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R 11  is C 3-7 cycloalkyl, heterocycloalkyl, heteroaryl, C 3-7 cycloalkylC 1-4 alkyl, heterocycloalkylC 1-4 alkyl, arylC 1-4 alkyl or heteroarylC 1-4 alkyl each optionally substituted with one or more C 1-4 alkyl, amino, C 1-4 alkylamino, diC 1-4 alkylamino, aminoC 1-3 alkyl, C 1-4 alkylaminoC 1-3 alkyl, diC 1-4 alkylaminoC 1-3 alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;  
 
 R 7  is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, (C 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, (diC 1-3 alkylaminoC 1-3 alkyl)(C 0-3 alkyl)amino, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC 1-4 alkyl, C(O)OH, acetamido or heterocycloaklyl groups, or with a phenyl group which is optionally substituted with one or more C 1-3 alkoxy, halogen, CF 3 , CF 3 O, hydroxy, C 1-3 alkyl, amino, C 1-3 alkylamino, diC 1-3 alkylamino, C 1-3 alkylaminoC 1-3 alkyl, diC 1-3 alkylaminoC 1-3 alkyl, C 1-3 alkylthio, aminocarboxy, C 1-3 alkylcarbonyl, ureido optionally substituted with C 1-3 alkyl, C(O)OC, 1-4 alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups; and  
 R 8  is H;  
 said method comprising: 
 (a) reacting the compound of formula (II) with a nitrile of the formula R 7 CN in the presence of a strong base in a suitable solvent to form a compound of formula (III):  
                     
 (b) reacting the compound of formula (III) with a suitable chlorinating agent to form the compound of formula (IV):  
                     
 (c) reacting the compound of formula (IV) with an alcohol of the formula HO(R 10  ) in the presence of a suitable base in a suitable solvent to provide the desired compound of formula (I) wherein R 5  is OR 10  and R 8  is H: